Investigating neuroinflammatory and neuronal mechanisms underlying the adverse neurological effects of brain radiotherapy

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Glioblastoma (GBM) is the most commonly occurring primary brain tumour and is a cancer of extreme unmet need. While clinical outcomes remain poor, overall survival has risen over the past 20 years, revealing the devastating impact of treatment-associated neurological complications. Radiotherapy (RT) is the most effective non-surgical treatment modality used in GBM and is a crucial component of standard of care for the majority of patients. RT is an effective treatment but causes irreversible cognitive impairments that worsen over time. Understanding the mechanisms underlying RT induced cognitive impairment will allow us to directly target this clinical unmet need in patients. Higher order brain functions such as cognition rely on the integrity of local and global neural synchrony and are mediated by GABAergic networks. GABAergic interneurons are strongly implicated in pathological states associated with cognitive dysfunction, with deficits in the parvalbumin interneuron (PVI) subset correlating with cognitive decline across multiple disease models. Our previous investigations (including both clinical and preclinical studies) have implicated these PVIs in the cognitive deficits associated with both schizophrenia and Alzheimer's disease. In the current project, we plan to undertake longitudinal behavioural, electrophysiological and quantitative post-mortem (immunohistochemical and automated western detection) studies to investigate mechanisms underlying cognitive deficits following RT treatment. A further aim of the project will be to evaluate the impact of rationale pharmacological interventions (targeting neuroinflammatory and GABAergic systems) to prevent/reverse the neurotoxic effects of brain RT